DE1670143A1 - 2- [Indolinyl (1 ') methyl] imidazoline (2) and its salts and processes for the preparation of these compounds - Google Patents

Description

2- / indolinyl (1 ') -methyl7-imidazoline (2) and its salts and processes for the preparation of these compounds. The invention relates to a new 2- [indolinyl (1') -methyl7-imidazoline (2) of the formula and its salts, which differ from known, similarly structured compounds by virtue of their particularly high therapeutic effectiveness and, at the same time, improved tolerability (reduced toxicity).

The new 2- [indolinyl (1 ') -methyl] imidazoline (2) from formula (I) can according to one embodiment of the invention are thereby produced. that one indoline with 2-halomethyl-imidazoline (2 or mreloo with 2-chloromethyl-imidazoline (2), and in the presence of an inert organiso @ en solvent, implemented.

The reaction can be carried out in a manner analogous to the reaction of chloroalkyl imidazolines, especially 2-chloromothylimidazoline (2), with the aliphatic, aromatic ones and heterocyclic series (Helvetina Chimion A @ ta, Vol. 33 (1950), 3. 1386 bic 1407) take place.

Because the arboiton with the froion 2-chloromethyl-imidazoline (2) -b bodingt by its easy decomposition, not comfortably irait, is preferred for the Implementation with the indoline anatollo dor troion Bano dao more resistant hydrochloride des 2-chloromethyl-imidazoline (2) is used. Dan hydrochloride of 2-chloromethyl-imidazoline (2) is therefore compared with the practical implementation of the method according to the invention the 2-chloromethyl-imidazoline (2), i.e. the free base, is preferred.

For the desolation of 2-chloromethyl-imidazoline (2) -hydrochloride with indoline, an ole ratio of the two reaction partners of 1 × 2 and above can be achieved be rooted. The implementation mentioned takes place in accordance with a preferred embodiment of the invention by heating for several hours (e.g. 2 to 10 Stundon) the reaction mixture in red organic solvent. In general, the Implementation at Tomperatures is carried out between 80 and 130 ° C. This is useful to the reflux temperature of the solvent orhitat.

Dan for the method according to the invention as a starting component 2-chloromethyl-imidazoline (2) -hydrochloride used can be carried out in a known manner Implementation of chloroacet-imidoethyl ether hydrochloride obtained with ethylenediamine (Helvetion Chimica Acta, Vol. 27 (1944), p. 1773).

As an inartefs organic solvent for the process according to the invention, alcohol, especially ethyl alcohol, has been found to be a special one. According to another embodiment of the invention, 2- [indolinyl (1 ') -methyl] -imidazoline (2) of the formula (I) can also be horgostellt by using a compound of the general formula (II) in which R the group -C # N, and R 'converts a lower alkyl radical, in particular a methyl or ethyl radical, with ethylenediamine, if appropriate in the presence of an inert organic solvent or diluent.

The implementation of the compound of general formula (II) in which R represents the group -CN, the indolinyl (I) acetonitrile, with ethylenediamine is expedient by heating an oinoB mixture of the two reaction partners for several hours carried out at a temperature of about 120 to 130 ° C. Amine is preferred here in excess, for example @ in an UboroohuQ of 50%, based on the applied, Calculated Honezo on indolinyl (1) acetonitrile is used. The @@@ is called less Amounts of carbon disulfide has been found to be useful in performing this process proved beneficial.

After eondetor reaction, then bot dissor Vmnotsunc annallende reaction product, the 2- [indolinyl (1 ') - methyl] imidazoline (2) of the formula (I), by distillation iooliort the reaction mixture. En is obtained in good yield.

Instead of the ethylenediamine in the form of the free base can be used for Reaction with the indolinyl (1) acetonitrile aucli dio salts of ethylenediamine, preferably the p-toluenesulfonic acid salt, can be used. In this case, Bonot will clwiohon Reajktionsbedingungen as when using ethylenediamine the molar ratio of Reaction partner chosen advantageously 1 @ 1. When implementing with the toluenesulfonmouron Sala dos Äthylendiamins is the raw product in the form of toluene sulfonate obtain. This can be further processed in such a way that one lasts orhalteno Salt dissolves in water, making the aqueous solution alkaline and leaving the dabai free set base, the 2- [indolinyl (1 ') - methyl] imidazoline (2) of the formula (I), then with a suitable organic solvent such as ether. dor The organic phase can be concentrated by means of anhydrous sodium sulfate the product is either distilled or converted into the by treatment with hydrogen chloride Hydrochloride has been borfuhyt.

P in this embodiment of the method according to the invention as Starting product used indolinyl (1) acetonitrile, for example, by reaction obtained from indalin with chloroacetanitrile in the presence of anhydrous sodium sar @ annt (see e.g. U.S. Patent 3,093,632, column 11, lines 27 to 35).

A compound of the general formula (II) in which R represents the grouping was chosen for the reaction with ethylenediemin bßdüutciundR * dieoLaajQbaiü &'ou.tuj'm.tt, for example, indolinyl (1) -a @ otiminoethyl ether in the form of hydrochloride, this reaction is carried out in the presence of an inert organic solvent by heating for several hours, preferably at the reflux temperature Solvent, carried out, the ethylenediamine in excess, preferably in an excess of 50%. is used. As an inert organic solvent, for example

Ethanol must be used. After filtering off the during implementation Ethylenediamine hydrochloride obtained in this way and concentration of the mother liquor the compound of the formula (I) can be obtained from the residue formed in the process by distillation can be obtained in pure form.

Indolinyl (1) acetiminoalkyl ethers can, for example, by acting from hydrogen chloride to a mixture of equivalent amounts of indolinyl (1) acetonitrile and a low molecular weight alcohol in the presence of an inert organic solvent, such as chloroform.

According to a further embodiment of the invention, the go, vünaohten nouets compound of the formula (I) can also be prepared by reacting ethylenediamine with a compound of the general formula (II) in which R is the grouping! and Rt denotes a niodoron alylrout, in particular a methyl or ethyl radical, b @, for example with indolinyl (1) - @@ ethyl acetate. This implementation can advantageously be carried out without the use of a solution or

Diluent by heating the gonic for several hours made both reactants to a temperature of about 120 bi @ 130 ° C will. @@ r the conversion of the indolinyl (1) -acetic acid alkyl ester with the ethylendlanine a molar ratio of 1.2 to 3 is preferably selected.

After the reaction has ended, the desired compound can be obtained Formula (I) from the reaction mixture by distillation isolioron * The ale Aungangsprodukt for this embodiment of the process according to the invention serving indolinyl (1) -ossig @ acid alkyl esters that have not yet been described. can through implementation of indoline with alkyl chloroacetate.

The respective reaction product is worked up in oil Wise and does not present any particular difficulties.

When using 2-chloromethyl-imidazoline (2) -t hlorids for the reaction with the indoline as a reaction product obtained hydrochloride of 2- [indolinyl (1 ') - methyl] -imidazolines (2) can e.g. by dissolving the hydrochloride in alcohol, adding sodium alcohol, Filter off the precipitated sodium chloride and evaporate the alcohol into the free life to be convicted. If necessary, the @ase Daa can be dealt with by rawhandling has been converted into their sal @ e with acids ..

The 2- [indolinyl (1 ') -methyl] -iniaasoline produced according to the invention (2) and its salt, especially the hydrochloride, have valuable therapeutic properties Properties, particular when used as a vasoconstrictor. They exhibit a pronounced abaShwollen effect on the mucous membrane and are therefore special as a means suitable for treating e.g. the nasal sinus in the case of colds.

The product of the process can be used both as such and in a forum gainer Sa, if necessary with suitable solid or liquid carriers, more commonly used Kind of ver @ ischt, for the production of pharmaceutical preparations such as solutions us veraprühen, ointments iytrnd derglaiohon, can be used.

The ubiquity deo nouen 2 - [Indolinyl (1 ') - methyl] inidazoline (2) hydrochloride with regard to the vasokenstrictive Effect on one known vasoconstrictor shows the following Table I, in which the with the said compound achieved results on the isolated rabbit ear in the arrangement according to KRAWKOW-PISSEMSKY (L. Ther: "Pharmacological Methods", Scientific Verlagsgeeellschaft, Stuttgart, 1949, pp. 193 to 195) can be compared with those those with the well-known 2- / 5 ', 6', 7 ', E'-tetrahydronaphthyl (1') - amino7-imidazoline (2) hydrochloride.

Table I. Dose 2- [indolinyl (1 ') - methyl] - 2- [5', 6 ', 7', 8'-tetrahydronaphthyl (1 ') - imidazoline (2) hydrochloride amino] imidazoline (2) hydrochloride in # Vasoconstriction duration (min) n vasoconstriction duration (min) n tion (%) tion (%) 1 100 # 9.6 24.2 # 6.8 21 100 # 7.6 17.7 # 4.2 21 0.1 98.7 # 11 11.02 # 3.8 16 93 # 7.4 6.5 # 1.9 20 0.01 65 # 5.8 1.87 # 0.39 16 8.8 # 0.9 0.33 # 0.07 19 ~ 1-- 0.001 15 # 3.1 1.01 # 0.2 17 no longer effective % @ Pre-reduction of the flow of a bicarbonate-containing Ringer's solution at 37 ° C compared to the initial value; The duration of the effect was assessed as the time within which the target effect had declined to 50%.

+ -Standard variation n-number of attempts GrUßerc @ lengen as 1 @ the compound that was horgeatollten according to the invention resulted in a complete and ao la persistent vasoconstriction, that even after waiting for more than an hour Output flow was not reached again.

From Tabolle I clearly shows that the inventively produced Compound is both stronger and much longer effective than the known Comparison substance, the 2- [5 ', 6', 7 ', 8'-tetrahydronaphthyl (1') amino] imidazoline (2) hydrochloride.

In Table II below, the am isolated rabbit ear determined ED50 (calculated according to LITCHFIELD and WIL @ OXON "J.Pharmacol. Experimental Therapeutics "96 (1949), pp. 99-113) of the 2- [indolinyl (1 ') -methyl] -imidazoline (2) -hydrochloride prepared according to the invention (A) compared to: 1 ißerhamiao-like structure Vorindunc, boider i In contrast to the compound obtained according to the invention, no indoline but the Tetrahydroquinoline residue available, i.e. only one ring expansion from the 5- to the 6-ring has taken place, the one described in: Holvetin Chimioa Aota, Vol,, 33 (1950): 2- [1 ', 2', 3 ', 4'-Totrahydroohinolyl (1') -methyl] -imidazoline (2) -hydrochloride (B) (cf. Tabel @ e 6, p. 1405, last of the listed connections).

2 with two known vasocene strictorone, 2- (2 ', 6'-dimethyl-4'-tert-butyl-phenyl-methyl) -imidazoline (2) -hydrochloride (C) and the 2- [1 ', 2', 3'4'-tetrahydronaphthyl (1 ')] - imidazoline (2) hydrochloride (D).

In Table II, the acute toxicity determined in mice and the toxicity threshold are also listed in the right-hand part. Table II Rabbit @ hr mice ED50 *) Number of LD50 (3 Tgé) Toxicity number Preparation threshold in mg / kg of (mg) Experiments orally mg / kg animals A 0.12 40 860 # 500 50 (0.08-0.16) (710-1040) B 0.60 32 780 # 500 50 (0.42-0.85) (630-960) C 0.46 28 490 # 300 60 (0.35-0.60) (390-610) D 2.61 30 480 # 200 50 (2.14-3.20) (400-580) *) Limits for 19/20 probability in brackets. Table II shows that the compound produced according to the invention is clearly superior to the known Torglolohseubatansen both in terms of vasoconstrictive action and in terms of tolerability.

The invention is explained in more detail below with the aid of examples.

Example 1 A Gemicoh of 46.5 g (0.3 mol) of 2-chloromethyl-imidazoline (2) hydrochloride, 71.5 g (0.6 mol) of indoline and 300 cm3 of absolute ethyl alcohol 7 B «doof liked at the reflux.

The entetohonde brown solution is concentrated in a vacuum to dryness, After the residue has been dissolved in 100 cm3 of water, 20 cm3 of 40% strength are added with cooling Add caustic soda. The aqueous DO is separated off and the organic phase with 600 cm3 of ether in front. The hydrochloride precipitates in a yield of 60 ß ts = 84%) from 2- [indolinyl (1 ') methyl] imidazoline (2) in flakes (melting point 206-207 ° C, corr.).

The hydrochloride can be recrystallized from alcohol for cleaning Calculated: C = 60.62% H = 6.78% N = 17.68% Cl = 14.92% Found: C = 60.38% H = 6.74% N = 17.63% Cl = 15.13% DA base is obtained from the solution of the purified hydrochloride in ethyl alcohol by adding sodium alcoholate, filtering off the precipitated Sodium chloride and evaporation of alcohol isolated. It shows after recrystallization has taken place from cyclohexane a melting point of 84-85 ° C (corr.).

Example 2 221.5 g (1.4 mol) of indolinyl (1) acetonitrile (melting point: 39 to 42 ° C) with 126 g (2.1 mol) of anhydrous ethylenediamine after addition of 6 cm3 of purified sulfur carbon dioxide using an oil bath for 4 hours heated to a temperature of 125 ° C estiva. Thereby strong ammeniac formation occurs on. When the reaction has ended, the reaction mixture is distilled. It will initially as a distillate anfallanda excess ethylenediamine separated as a forerun.

The 2- [indolinyl (1 ') - methyl] imidazoline (2) then distills under a pressure of 0.4 mm at a temperature of 154 to 160 00 Uber * Yield: 260 g (= 92% of theory) Example 3 A mixture of 15.8 g # (0.1 mol) indolinyl (1) acetonitrile and 23.2 g (0.1 mol) of mono-p-toluenesulfonate of ethylenediamine Heated for several hours to about 125 ° C, until no more ammonia development occurs. The cooled reaction mixture is then dissolved in water, and so is the aqueous solution is freed from impurities by shaking with ether. Au the watery Solution is then through Add about 5 cm3 of 40% sodium hydroxide solution the 2- [indolinyl (1 ') - methyl] imidazoline (2) precipitated as the free base. The Dase will dissolved in ether, and the ether phase dried with anhydrous sodium sulfate with ethereal hydrochloric acid. The hydrochloride of the falls 2- [Indolinyl (1 ') -methyl] -imidazoline (2), which after suction filtration and drying is obtained. For purification, the hydrochloride can be recrystallized from alcohol (melting point: 206 to 207 ° C).

Example 4 A mixture of 27.7 g (0.1 mol) of indolinyl (1) acetiminoethyl ether hydrochloride (produced by introducing dry hydrogen chloride gas for three hours low tpontur in a mixture of equivalent amounts of indolinyl (1) acetonitrile and absolute @thanol in Gogenwart from waaoorfoioa Xorotorn), 9.0 g (0.15 mol) anhydrous a'thymendiamine and 120 cm3 of absolute ethanol is about 18 hours heated to reflux. After filtering off the ethylenedinine hydrochloride obtained during the roaction and distilling off the ethanol, the remaining 2- [indolinyl (1 ') - methyl] imidazoline (2) boils under a pressure of 0.2 mm at a temperature of 159io610.Dohaelauhktt70bia79 <5 ° C.

* Example 5 e a) 24.5 g (0.2 mol) of ethyl chloroacetic acid @@@@ r werdne with 47.0 g (0.395 mol) indoline 1 1/2 hour @ @@@ @@@@ @ @ heated. After the end of the reaction, the precipitated crystals are dissolved in about 60 cm3 of water dissolved and the remaining oil is absorbed in ether. The ether phase is treated with activated charcoal, filtered and then with anhydrous sodium sulfate stretched. After the ether has been distilled off, the indolinyl (1) ethyl acetate can be obtained Isolate duroh distillation. It boils at 170 to 180 ° C / 22 @@. b) 8.2 g (0.04 mol) of the indolinyl (1) ethyl acetate hergestollton according to a) are mixed heated to 130 ° C for about 18 hours with 7.2 g (0.12 mol) waQOorfroiom ethylenediamine The 2- [indolinyl (1 ') - methyl] imidazoline (2) which passes over after the excess ethylenedi @@@ has been distilled off can anxohlieCend sus further purification of a second distillation beL 225 bis 232 ° C / 22 mm.

Claims (4)

Patent claims 2- [indolinyl (1 ') -methyl] -imidazoline (2) of the formula and its Salse. 2 Process for the preparation of 2- [indolinyl (1 ') - uethyD-imidazoline (2) of the formula and dousen salt, characterized in that indoline with 2-halomethyl-imidazoline (2), besenders with 2-chloromethyl-imidazoline (2) hydrochloride or a compound of the general formula II in which R dio group un4 R 'denotes a lower alkyl radical, in particular a methyl or ethyl radical, is reacted with ethylenediamine or its salt derivatives, in the presence of an inert solvent or diluent. 3. Method according to Anapruoh li daduroli sokonnzoichnot that one ala If necessary, alcohol is also used. 4. Ancestors according to Anapruoh 1 or 2, daduroh marked that the reaction is carried out at temperatures of about 80-0.